Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality worldwide. The currently available treatments are largely palliative and have minimal impact on the inflammatory process in COPD that inexorably leads to a decline in lung function. Unlike asthma, for which inhaled corticosteroids are a highly effective treatment, COPD appears to be a largely steroid- resistant disease. Therefore, there is a pressing need to develop drugs that also target other components of the disease, mainly airway inflammation and remodeling. By reducing airway resistance and aspects of inflammation, Rho kinase inhibitors represent a novel approach to provide symptomatic improvement and slow the progression of the disease. Our overall objective is to develop an inhaled, safe and efficacious ROCK inhibitor as maintenance therapy for airflow obstruction in patients with COPD, including chronic bronchitis and emphysema. Theron has identified a highly potent inhibitor of the human ROCK-1 and ROCK-2 isoenzymes. The purpose of this proposal is to further characterize the lead inhibitor TRN-101 in models that are relevant to airway resistance, inflammation and remodeling. The specific aims of this phase I proposal are: 1) to demonstrate the bronchoprotective effect of an inhaled ROCK inhibitor, TRN-101, against methacholine-induced bronchospasm in anaesthetized rats;and 2)to evaluate the effects of TRN-101 on airway inflammation using an in vivo mouse model of COPD exacerbation. The latter study will focus on the effects of an inhaled ROCK inhibitor on neutrophil trafficking in the airways of mice challenged with lipopolysaccharide (LPS). By achieving the specific aims outlined above, we believe Theron Pharmaceuticals can advance a novel pharmacological treatment for COPD. Because of the potential anti-inflammatory activity and impact on tissue remodeling, ROCK inhibitors could offer unprecedented benefits for the treatment of this disease. PUBLIC HEALTH RELEVANCE: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality worldwide. The current available treatments are largely palliative and have minimal impact on the inflammatory process in COPD that leads to an inexorable decline in lung function. By reducing airway resistance and aspects of inflammation, Rho kinase inhibitors represent a novel approach to provide symptomatic improvement and to slow the progression of the disease. Our overall objective is to develop an inhaled, safe and efficacious ROCK inhibitor as maintenance therapy for airflow obstruction in patients with COPD, including chronic bronchitis and emphysema.